**3. Cardiovascular disease**

The high impact that T2DM has on the CVD has generated numerous studies, and population analyzes in order to determine the prevalence of the cardiovascular pathologies in people with diabetes. Although the description and the diagnostic criteria used to define the different manifestations of CVD were different across the epidemiologic studies, overall, the results show that CVD is a major cause of comorbidity and mortality among patients with T2DM. Thus, the CVD, including myocardial infarction, stroke, angina, heart failure, atherosclerosis and coronary artery disease, is present in 32.2% of people with T2DM. The most frequent type of CVD seems to be the CAD (21.2%), males having higher rates (18.7%) than females (14.3%) [21]. A large cohort of 1,921,260 individuals, 1.8% with T2DM, followed 5.5 years, has been analyzed in terms of the most common initial manifestations of CVD. In T2DM individuals, peripheral artery disease was the most frequent first presentation (16.2%) followed by HF (14.1%), significantly higher compared with those without diabetes [22]. The prevalence of CVD and the incidence of primary adverse outcomes is higher in women with T2DM than their male counterparts (RR = 9.29; P < 0.0001 for CVD and RR = 5.25; P < 0.0001 for incident major adverse outcomes [23]. Data from the UK Biobank showed that a cardiovascular event's excess risk was approximately 50% higher in women (HR = 1.96) than in men, and more importantly, the incidence of myocardial infarction (MI) [A1] was higher in men than in women(28.8%). This observation was exciting since the sex differences were the same in all age-related groups and were attenuated with increasing age, from 0.27 (0.18 to 0.41), in 45 years age cluster versus 0.45 (0.40 to 0.50) in 65 years age cluster. [24].

**281**

*Cardiovascular Risk/Disease in Type 2 Diabetes Mellitus DOI: http://dx.doi.org/10.5772/intechopen.97422*

individuals with diabetes mellitus.

ventricular pressure [28].

HF and CV mortality [16].

patients without these diseases [29].

higher in patients with eGFR <60 ml/min/1.7 m2

Although diabetes-related excess mortality is lower in the contemporary era than previously, T2DM is associated with a two to six times increased risk of CVD mortality than people without diabetes. Cardiovascular disease accounts for 52% of deaths in type 2 DM [25]. MI is considered to be the main cause of death for

T2DM is a significant predictor of HF, independent of the simultaneous presence of hypertension and coronary heart disease. In diabetes, HF has multiple risk factors: hyperglycemia, insulin resistance, age, ischemic heart disease, high blood pressure, left ventricular hypertrophy, diffuse, accelerated and severe atherosclerosis. Even in the absence of CAD, microvascular complications, arterial thickening and fibrosis, endothelial and vasomotor dysfunction, increase the risk of HF. The risk of HF is 2–4 times higher in men and five times higher in women compared to those without diabetes, according to Framingham Heart Study [5, 16]. The presence of DM in those hospitalized for HF worsens the prognosis, prolongs hospitalization, and increases the number of hospitalizations and the risk of death. In stable forms of HF, T2DM is an independent predictor of hospitalization and mortality, regardless of the ejection fraction [26]. Patients with T2DM have a 2.5-fold increased risk of developing HF and a 75% higher risk of CV

HF with preserved ejection fraction (HFpEF) is a frequent phenotype in T2DM and is related to an important risk of morbidity and mortality than those without diabetes, with multiple comorbidities, reduced exercise capacity, increased markers of inflammation, fibrosis, endothelial dysfunction, congestion, increased left

At similar ejection fraction values, patients with T2DM have a higher NYHA functional class, and more expressed symptoms than those without diabetes. Left ventricular (LV) diastolic dysfunction can be detected in approximately 75% of patients with T2DM, even in the early stages. The degree of hyperglycemia and its duration correlate with LV diastolic dysfunction's severity, with the increased risk of

A retrospective cohort study that included 208,792 adults with diabetes has analyzed the impact of varying combinations of heart disease, stroke, moderate chronic kidney disease (CKD) on mortality, over a median follow-up of 8.5 years [29]. The effect of heart diseases, stroke, CKD, and the combination of these

conditions on all-cause mortality has been found to be independent and cumulative. The mortality risks were 1.75 times, 2.63 times, and 3.58 times greater for patients with one, two, and all three above mentioned conditions, and life expectancy for a 40-year-old with one, two, and three conditions was reduced with 20, 25, and 30 years for men and 25, 30, and 35 years, respectively, for women, compared with

Diabetes is the most known cause of CKD, and end-stage renal disease, more than 50% of people with DM are likely to develop CKD. CKD, especially severe CKD, has a significant impact on life expectancy and mortality risk in patients with diabetes. The risk of CV death increases as renal function declines (eGFR <60 ml/min/1.73 m2

ACR (albumin-creatinine ratio) ≥10 mg/g) [30]. Rates of HF are approximately 3-times

The CardioRenal Metabolic Syndrome (CaReMe) has been introduced as terminology to describe the ongoing relationship between obesity, diabetes, kidney disease and heart failure with preserved systolic function, with significant

Within CVD, diabetic cardiomyopathy or "cardiac microvascular disease", is a phenotype with distinct manifestations, described as a "structural and

functional alteration of the myocardium, in the absence of hypertension, ischemic

mortality implications rate and therapeutic interventions [32].

[31].

and/or

mortality or hospitalization for HF than those without DM [27].

*Type 2 Diabetes - From Pathophysiology to Cyber Systems*

(www.advanceriskengine.com) [18].

risk factors and mortality [20].

**3. Cardiovascular disease**

0.50) in 65 years age cluster. [24].

therapeutic goals and interventions.

appropriate treatment. For practice, CVR assessment scores which can be applied in diabetes are beneficial. Several CVR calculation scores in DM have been developed. The first is the result of the United Kingdom Prospective Diabetes Study (UKPDS), in which, in people newly diagnosed with T2DM, the effect of intensive treatment on the evolution of chronic complications compared to conventional treatment was followed. UKPDS Risk Engine estimates the risk of fatal and non-fatal coronary events and fatal and non-fatal stroke at 15 and 30 years, in people with T2DM without CV disease, considering the duration of DM, age, gender, ethnicity, smoking, presence of atrial fibrillation, the level of HbA1c, systolic blood pressure,

total cholesterol and HDL-C (https://www.dtu.ox.ac.uk/riskengine/) [17]. Another score (Advance Risk Engine) is based on ADVANCE and

(available online at tools.acc.org/ASCVD-Risk-Estimator-Plus) [19].

ADVANCE-ON studies. It refers to patients with T2DM without CVD, is based on the usual parameters and estimates the risk of major CV events at four years, the risk of renal events at five years and the risk of major vascular disease at ten years

The American Heart Association (AHA) and American College of Cardiology (ACC), developed a risk score to estimate the ten-year risk for the first ASCVD event (non-fatal myocardial infarction or CHD death, or fatal/non-fatal stroke)

Based on the ACCORD trial population, the BRAVO risk engine has been recently developed. It contains three separate modules addressed to events (stroke, MI, HF, angina, revascularization surgery, renal events, blindness, hypoglycemia),

None of these CVR estimation scores is perfect, so clinical judgment and consideration of CVR factors are important for setting and selecting appropriate

The high impact that T2DM has on the CVD has generated numerous studies, and population analyzes in order to determine the prevalence of the cardiovascular pathologies in people with diabetes. Although the description and the diagnostic criteria used to define the different manifestations of CVD were different across the epidemiologic studies, overall, the results show that CVD is a major cause of comorbidity and mortality among patients with T2DM. Thus, the CVD, including myocardial infarction, stroke, angina, heart failure, atherosclerosis and coronary artery disease, is present in 32.2% of people with T2DM. The most frequent type of CVD seems to be the CAD (21.2%), males having higher rates (18.7%) than females (14.3%) [21]. A large cohort of 1,921,260 individuals, 1.8% with T2DM, followed 5.5 years, has been analyzed in terms of the most common initial manifestations of CVD. In T2DM individuals, peripheral artery disease was the most frequent first presentation (16.2%) followed by HF (14.1%), significantly higher compared with those without diabetes [22]. The prevalence of CVD and the incidence of primary adverse outcomes is higher in women with T2DM than their male counterparts (RR = 9.29; P < 0.0001 for CVD and RR = 5.25; P < 0.0001 for incident major adverse outcomes [23]. Data from the UK Biobank showed that a cardiovascular event's excess risk was approximately 50% higher in women (HR = 1.96) than in men, and more importantly, the incidence of myocardial infarction (MI) [A1] was higher in men than in women(28.8%). This observation was exciting since the sex differences were the same in all age-related groups and were attenuated with increasing age, from 0.27 (0.18 to 0.41), in 45 years age cluster versus 0.45 (0.40 to

**280**

Although diabetes-related excess mortality is lower in the contemporary era than previously, T2DM is associated with a two to six times increased risk of CVD mortality than people without diabetes. Cardiovascular disease accounts for 52% of deaths in type 2 DM [25]. MI is considered to be the main cause of death for individuals with diabetes mellitus.

T2DM is a significant predictor of HF, independent of the simultaneous presence of hypertension and coronary heart disease. In diabetes, HF has multiple risk factors: hyperglycemia, insulin resistance, age, ischemic heart disease, high blood pressure, left ventricular hypertrophy, diffuse, accelerated and severe atherosclerosis. Even in the absence of CAD, microvascular complications, arterial thickening and fibrosis, endothelial and vasomotor dysfunction, increase the risk of HF. The risk of HF is 2–4 times higher in men and five times higher in women compared to those without diabetes, according to Framingham Heart Study [5, 16].

The presence of DM in those hospitalized for HF worsens the prognosis, prolongs hospitalization, and increases the number of hospitalizations and the risk of death. In stable forms of HF, T2DM is an independent predictor of hospitalization and mortality, regardless of the ejection fraction [26]. Patients with T2DM have a 2.5-fold increased risk of developing HF and a 75% higher risk of CV mortality or hospitalization for HF than those without DM [27].

HF with preserved ejection fraction (HFpEF) is a frequent phenotype in T2DM and is related to an important risk of morbidity and mortality than those without diabetes, with multiple comorbidities, reduced exercise capacity, increased markers of inflammation, fibrosis, endothelial dysfunction, congestion, increased left ventricular pressure [28].

At similar ejection fraction values, patients with T2DM have a higher NYHA functional class, and more expressed symptoms than those without diabetes. Left ventricular (LV) diastolic dysfunction can be detected in approximately 75% of patients with T2DM, even in the early stages. The degree of hyperglycemia and its duration correlate with LV diastolic dysfunction's severity, with the increased risk of HF and CV mortality [16].

A retrospective cohort study that included 208,792 adults with diabetes has analyzed the impact of varying combinations of heart disease, stroke, moderate chronic kidney disease (CKD) on mortality, over a median follow-up of 8.5 years [29]. The effect of heart diseases, stroke, CKD, and the combination of these conditions on all-cause mortality has been found to be independent and cumulative. The mortality risks were 1.75 times, 2.63 times, and 3.58 times greater for patients with one, two, and all three above mentioned conditions, and life expectancy for a 40-year-old with one, two, and three conditions was reduced with 20, 25, and 30 years for men and 25, 30, and 35 years, respectively, for women, compared with patients without these diseases [29].

Diabetes is the most known cause of CKD, and end-stage renal disease, more than 50% of people with DM are likely to develop CKD. CKD, especially severe CKD, has a significant impact on life expectancy and mortality risk in patients with diabetes. The risk of CV death increases as renal function declines (eGFR <60 ml/min/1.73 m2 and/or ACR (albumin-creatinine ratio) ≥10 mg/g) [30]. Rates of HF are approximately 3-times higher in patients with eGFR <60 ml/min/1.7 m2 [31].

The CardioRenal Metabolic Syndrome (CaReMe) has been introduced as terminology to describe the ongoing relationship between obesity, diabetes, kidney disease and heart failure with preserved systolic function, with significant mortality implications rate and therapeutic interventions [32].

Within CVD, diabetic cardiomyopathy or "cardiac microvascular disease", is a phenotype with distinct manifestations, described as a "structural and functional alteration of the myocardium, in the absence of hypertension, ischemic coronary heart disease, valvulopathies, or other FRCV, in patients with diabetes, especially with long-term diabetes and poor control." Fibrosis, stiffness, and cardiac hypertrophy are basic changes, which are initially associated with diastolic dysfunction, LV hypertrophy and reduced compliance with preserving the ejection fraction, later evolving into systolic dysfunction clinically manifest HF [16, 33]. As risk factors of diabetic cardiomyopathy, hyperglycemia, dyslipidemia, altered energy metabolism, dysregulated insulin signaling, inflammation, endoplasmic reticular stress, mitochondrial dysfunction, oxidative stress and accumulation of advanced glycation end-products (AGEs) and activation of the renin-angiotensinaldosterone system (RAAS) are described [33].
